Systolic heart failure (HF) is an increasing contributor to disease burden and healthcare expenditure in the United States. Approximately 5 million Americans have heart failure and 550,000 new cases are reported annually. 42% of cases end in mortality within 5 years of admission for heart failure. Congestive heart failure (CHF) is a significant public health problem with more than 20 million people affected worldwide. The prevalence of CHF is on the rise with increasing incidences of coronary artery disease, particularly amongst an aging population in the United States.
Patients with HF who have delayed depolarization of the lateral wall of their left ventricle (LV) have impaired contractile function due to dyssynchronous electrical and mechanical activation. Dyssynchronous heart failure (DHF) is associated with abnormal wall stress and alteration of gene expression differentially between the late-activated lateral wall and early-activated anterior wall. One contributor to left ventricular dysfunction and CHF is ventricular dyssychrony. Dyssynchronous ventricular contractions occur as a result of damage to the heart's conduction system due to cardiomyopathy, ischemic damage, or pacing. The myocardium in the late-contracting areas is subjected to increased wall stress, decreased coronary perfusion, and up-regulation of genes involved in cardiac hypertrophy, fibrosis, and apoptosis. Ventricular dyssynchrony has been shown to lead to a decline in cardiac function and approximately 35-50% of medication-refractory heart failure patients have evidence of dyssynchrony.
Treatments for HF include administration of beta-blockers, which decreases mortality by 30-35%; or administration of ACE inhibitors, which decreases mortality by 16-30%. While large clinical trials have shown that medications and device-based therapies lead to improved outcomes in patients with HF, a significant proportion of patients do not adequately respond to these therapies, e.g., 50-60% of patients, have medication refractory HF. Generally, patients with impaired contractile function due to dyssynchronous left ventricular (LV) electrical and mechanical activation (termed dyssynchronous heart failure, DHF) benefit from cardiac resynchronization therapy (CRT) by simultaneously pacing their septal and lateral LV. CRT has been shown to decrease CHF hospitalizations, improve quality of life and CHF symptoms, and decrease mortality. Current guidelines indicate that CRT should be used in patients with symptomatic CHF (New York Heart Association (NYHA) Class II-IV), a low ejection fraction (EF) less than 35%, and a QRS duration >130 ms. Unfortunately, even in appropriately selected patients, approximately 30% of patients do not derive benefit from CRT, and algorithms to predict response to CRT using currently available clinical and biochemical variables have not been satisfactory. Therefore, novel approaches for predicting response to CRT are urgently needed, and would help identify patients who would benefit from this procedure.
Although retrospective studies have identified some clinical variables such as diabetes, female gender, and QRS duration on the ECG, as predictors of response to CRT, none of these variables can adequately explain differences between responders and non-responders. Thus there is a need in the field for methods that can predict whether a patient will be a ‘responder’ or a ‘non-responder’ to a cardiac therapy, e.g., cardiac resynchronization therapy, in order to better determine a treatment course for the patient.